Hydroxyalkyl fluorenyl amines



Patented Oct. 30, E951 HYDROXYALKYL FLUORENYL AMINES George Rieveschl,J12, Grosse Pointe Woods. Mich., assignor'to Parke, Davis & Company,Detroit, Mich., a corporation of Michigan No Drawing. Application April11, 1949,

Serial No. 86,869

This invention relates to a new class of alcohols and to methods forobtaining the same. More specifically, the invention relates tosubstituted 9-fluoreny1 p-hydroxyalkyl amines and their acid additionsalts. The free base compounds of the present invention have theformula,

where R is a lower alkyl or lower alkenyl radical and R1 is hydrogen ormethyl.

In accordance with the invention the new amino alcohols may be obtainedas a free base having the formula given above or as an acid additionsalt of the base with an inorganic or organic acid. Some examples of thesalts which may be prepared by the methods hereinafter described are thehydrochloridefl liydrobromide, hydroiodide, sulfate, sulfamate,phosphate, acetate, citrate, oxalate, succinate, benzoate, tartrate,picrate, phthalate, maleate,-oleate and the like.

It has been found that thecompounds of the present invention may beobtained by several different methods. For example, they may be preparedby the reaction of a 9-fluorenyl halide and an alkyl or alkenylp-hydroxyalkyl amine. The reaction is preferably carried out in an inertorganic solvent such as benzene, toluene or xylene. A modification ofthis process involves the use of an alkaline material to react with themineral acid formed during the reaction. When the reaction is carriedout in the presence of such materials a smaller quantity of amine isrequired since the amine is not removed from the reaction by saltformation. In general, when no acid binding agent is employed, it ispreferable to use about two or more equivalents of amine for eachequivalent of the 9-fluorenyl halide. Some of the alkaline substanceswhich can be used in the process are alkali metal hydroxides, oxides,

alcoholates, carbonates, bicarbonates, acetates and the like. Thealkaline earth metalhydroxides, oxides and carbonates may also be used.

Alternatively, a 9-flu0reny1 alkyl or alkenyl amine can be reacted witha fl-hydroxalkyl halide 1 under substantially the same conditions asdescribed above for the reaction of a 9-fluorenyl halide with an alkylor alkenyls-hydroxyalkyl amine. Still another method for obtaining thesenew tertiary amino alcohols consists in reacting 8 Claims. (01. 260-576)ethylene oxide or 1,2-propylene oxide with a. 9- fluorenyl alkyl oralkyenyl amine in an inert organic solvent such as methanol, ethanol,benzene, toluene, xylene, dioxane and the like.

The substituted 9-fluorenyl s-hydroxyalkyl amines and their acidaddition salts are useful in the preparation of other organic compoundsand find particular use in the preparation of sympatholytic agents.

The invention is illustrated by the following examples.

Example 1.-9-florenyl methyl s-hydroaiyethyl amine organic layerseparated. The organic layer is extracted with dilute hydrochloric acid,the acidic aqueous extracts made alkaline with sodium hydroxide andthemixture extracted with ether. The ether extract is dried over potassiumcarbonate and the ether distilled in vacuo to obtain the desired9-fiuorenyl methyl ,B-hydroxyethyl amine.

Example 2.9-fluoenyl ethyl s-hydroxyethyl amine ture is refluxed for anadditional eight and one-- half hours, cooled and diluted with ether.The 1 reaction mixture is washed with saturatedsodium picric acidsolution and the resulting mixtures.

diluted with ether. The crystals. which separate are collected andpurified by recrystallization from methanol. The melting: pointof thepicrate; salt thus obtained is 136 Treatment of the free base of theaminot'alx-il5'r cohol with an excess of hydrogen chloride on. hydrogenbromide in isopropanol or ether yields'e the hydrochloride andhydrobromide salts respectively.

Example. 3..9 :JLuorenyl ;zsopropyl e-hydxom'y ethyl. amine i omens?18.6 g, of isopropyl .ethanolamine and g, .of potassium carbonate in50cc. of xylene is heated to boiling and g. of Q-fluorenyl chloride in150 ccaof xyl'eneadded zto -thewsolution with: stirring over a period oftwo hourss. After the addition has been completed, the reaction mixtureis refluxed foreight hours and then poured into 300 cc. of water. Thexylene layer is separated, washed with water, the: aqueous extractsdiscarded and then the organic layer extracted'with an excess of dilutehydrochloric acid. The acidic aqueous extract is extracted once withether; the ether layer discarded and the aqueous solution made alkalinewith 20 g. ofsodium hydroxide. The yellow, oily product which rises tothe surface of the solution is" taken up' in-ether;- the-ethensoli'itiondried and the ether distilled to obtainthe desired free base of9'-fluorenyl isopropyl ,B-hydroxyethyl amine;

amine 21.7 g; of 9-fluorenyl chloride dissolved in 125 cc. of xylene isadded with stirring to a solution of 29 g. of butyl ethanol aminedissolved-in 50 cc. of xylene at refluxing temperature. After theaddition has been completed, about two hours, the reaction mixture isheated for an additional twelve hours. The reaction mixture is. cooled,the hygroscopic crystals of butyl ethanol amine hydrochloride removed byfiltration and the filtrate treated with v300 cc. of water. The organiclayer is diluted with ether, removed, washed with .iresh Water'and thenextracted with an excess of dilute. hydrochloric acid. The. aqueousacidic. extract ismadealkaline with sodium hydroxide and'extracted withether. The ether extract is dried. and the ether removed; bydistillationjnvacuoto. obtain theidesired 9-fluorenyln-butylfi-hydroxyethyl amine.

Example 5 .9-fluorenyl allyl e-hydroxyethyl amine v A solution of 101 g.of 9-fluorenyl chloride in 200 cc. of benzene is added to a refluxingmixture composed iofi55'g. of allyl ethanol amine and 55 g. of anhydroussodium carbonate in 300 cc. of benzene over. a... period of forty-five 7minutes.

Aitentheaddition-has been completed the mix- :ture is refluxed for sixhours, cooled and treated with 55cc; of water. The organic layer isseparated, extracted with several portions of dilute hydrochloric acidand the acidic extracts made alkaline with 20% potassium hydroxidesolution.

The free base of the product is extracted with ether, the etherextractsv dried and the. ether. distilled. The residue consists of thedesired. 9.-fluoreny l 'allyl ,B-hydroxyethyl amine.

Example :6;-9-fluorenyl n-hewyl e-hydroxyethyl? amine cmcmcmdmomcm Asolution of 235 g. of Q-fluorenyl bromide in ce-not, tolueneisaddedslowly to .-a;- refluxing.' solution of 300 g. of'anq-hexy1ethanol amine'ing 100 ,-cc.- vof tdluene and the solution refluxed foraetotalof six-hours; Theemi-xtu-re-is--coo1ed and, then-hexyl ethanolamine hydrobromide re-.= moved by. filtration. Distillationbf 'thesolvent; fromnthe filtrate yields.- the-desired free base of 9-.-fluorenyl'-n-.hexyl.fi-hydroxyethyl amine as a light..colored o1l.

Example 7.-9-fluorenyl methyl fl-h'ydrowypropyl' amine Example 8-,9-fluoreny l allyl p-hydromym'opyll amine.

of 10% potassium hydroxide solution. The free base which separates istaken up in ether, the ether solution dried and the ether evaporated toobtain the desired 9-fluorenyl allyl p-hydroxypropyl amine.

What I claim is:

1. A compound of the class consisting of a free base and its acidaddition salts, said free base having the formula,

where R is a member of the class consisting of lower alkyl and allylradicals and R1 is a member of the class consisting of hydrogen andmethyl.

2. A compound of the class consisting of a free base and its acidaddition salts, said free base having the formula H-N-CHnCH-OH where Ris lower alkyl and R1 is a member of the class consisting of hydrogenand methyl.

3. A compound of the formula,

where R is a lower alkyl radical.

. 9-fluorenyl ethyl ,B-hydroxyethyl amine.

. 9-iluorenyl isopropyl fl-hydroxyethyl amine. Q-fiuorenyl methylB-hydroxyethyl amine.

. 9-fiuoreny1 n-butyl B-hydroxyethyl amine. 9-fluorenyl n-hexylB-hydroxyethyl amine.

GEORGE RIEVESCHL, JR.

No references cited.

1. A COMPOUND OF THE CLASS CONSISTING OF A FREE BASE AND ITS ACIDADDITION SALTS, SAID FREE BASE HAVING THE FORMULA,